Differential effects of kappa opioid receptor activation and blockade on the development of methamphetamine-induced sensitization in adult male and female rats

Abstract

Over the last decade the illicit use and abuse of methamphetamine has increased in the United States. Repeated and intermittent use of methamphetamine can lead to sensitization of brain circuits, which can promote continued abuse of methamphetamine. However, neural substrates underlying methamphetamine-induced sensitization are not fully understood. In this proposal, we specifically evaluated the role of kappa opioid receptors (KORs) in the development of methamphetamine-induced sensitization in adult male and female rats. In animals, methamphetamine-induced sensitization manifests as enhanced behavioral response to a dose of methamphetamine after a period of repeated intermittent methamphetamine treatment compared to response to the same dose of methamphetamine prior to exposure to repeated methamphetamine treatment. The experiment was conducted over 28 days and locomotor activity (primary dependent measure) was measured on Days 1, 2, and 28. All animals received saline on Day 1. Animals then received methamphetamine (0.5 mg/kg; i.p.) on Day 2 and Day 28. Animals were treated daily with a single injection of methamphetamine (1 mg/kg; i,p,) for 6 days (Days 3-8; period of repeated intermittent exposure). Animals received no methamphetamine treatment between Days 9-27 (drug-free period). This drug-free period allows for methamphetamine-induced neurobiological changes to take place, which are hypothesized to play a role in the sensitized response to methamphetamine. To assess the role of KOR receptors, animals received a single injection of either the KOR agonist (U50488; 1.5 mg/kg; s.c.) or saline (1 ml/kg; s.c.; control) daily for 6 days (Days 3-8), 30 minutes prior to receiving methamphetamine (1 mg/kg; i.p.). Other groups of animals received either the KOR antagonist (norBNI; 15 mg/kg; s.c.) or saline (1 ml/kg; s.c.; control) on Day 2 after measurement of methamphetamine-induced locomotor activity. Animals received only one injection of the KOR antagonist (norBNI) because of its long duration of action (28 days). Data obtained from the study suggests that activation of the KORs using the KOR agonist (U50488; 1.5 mg/kg; i.p.) significantly decreased methamphetamine-induced sensitization in adult female, but not male rats, compared to respective controls. In contrast, blockade of the KORs using the KOR antagonist (norBNI, 15 mg/kg; s.c.) significantly increased methamphetamine-induced sensitization in adult male, but not female rats, compared to respective controls. Based on the data we can suggest an inhibitory role of KORs in the development of methamphetamine-induced sensitization in adult male rats, which was unmasked by blocking KORs prior to methamphetamine exposure. Together, the data suggest a sex-dependent differential role for KORs in the development of methamphetamine-induced sensitization in adult male and female rats.Dr. D'Souza was supported by an endowed fellowship (Pharmacy Centennial Alumni Chair) and a Bower, Bennett and Bennett summer grant awarded by the